This Clinical ACE application is driven by the hypothesis that organ-targeted autoimmune diseases are mediated by unique pathogenic interactions between cells of the immune system and parenchymal cells of the target organ, which play both afferent and efferent roles in disease initiation and target organ destruction. By understanding these disease-specific processes, new avenues to disease-specific treatment should come into view, along with novel biomarkers that reflect disease-specific interactions between lymphocytes and cells of the target organ. This hypothesis underlies the three proposed projects of this Clinical ACE. The Primary Clinical Project: Mechanistic studies of Phase III trial with BAF312 in Secondary Progressive Multiple Sclerosis, led by Yang Mao-Draayer, PhD, MD and Benjamin M. Segal, MD, will study the mechanisms of clinical benefit of a novel sphingosine-1-phosphate receptor modulator, focusing both on pathogenic T cell autoreactivity characteristic of MS, and on the ability of the damaged central nervous system to initiate repair and recovery from immune attack. The Alternate Clinical Project: Mechanistic studies of treatment of systemic sclerosis with Abatacept, led by Dinesh Khanna, MD, MS, with co-investigator David A Fox, MD, Robert Lafyatis, MD (Boston U), and Michael Whitfield, PhD (Dartmouth), will assess the effects of T cell co-stimulation blockade in scleroderema on both immune cell activation, and biomarkers of tissue damage and fibrosis in the skin. The Collaborative Project: Role of organ-specific parenchymal cells in human organ-targeted autoimmune diseases, led by Massimo Pietropaolo, MD, with co-investigators David A. Fox, MD, Roberto Gianani, MD, and Terry J. Smith, MD, will study target organ phenomena potentially involved in the initiation of autoimmune diabetes, rheumatoid arthritis and autoimmune thyroid disease, three conditions that cluster epidemiologically. The Administrative Core and overall project will be led by David A. Fox, MD, who has two decades of experience in directing multidisciplinary NIH-funded center grant awards.